On October 24, 1971 while playing for the Detroit Lions, he suffered a fatal heart attack during the final minutes of a game against the Chicago Bears at Tiger Stadium in Detroit. He had run a pass route but was not part of the play, an incomplete pass intended for Lions tight endCharlie Sanders. He was jogging back to the huddle when he collapsed on the Bears' 15-yard line without contact.[3] Initially some thought he was faking an injury to stop the clock, but when Bears linebackerDick Butkus frantically signalled for help on the field,[6] it was obvious that he was in serious trouble, and the game, which the Bears won 28-23, was finished in near silence. His teammates were informed of his death before leaving the stadium. Hughes, as it turned out, suffered from advanced arteriosclerosis. The autopsy revealed that his coronary arteries were 75% blocked and that he was killed by a blood clot that completely cut the circulation to his heart muscle.[7] His family had a history of heart problems.[8] Hughes was buried in San Antonio, Texas, and all 40 of his Lions teammates attended his funeral, including head coach Joe Schmidt.[4] He is survived by his widow, Sharon Leah, and his son, who was 1 year and 11 months old at the time, Brandon Shane.[3] A $10,000 trust fund was set up for his son Brandon by an insurance company.[9] His widow filed a $21.5 million malpractice lawsuit against Henry Ford Hospital in 1972 for not diagnosing his condition when he was hospitalized after complaining of chest pains. The lawsuit was settled on October 3, 1974 for an undisclosed amount of money.[10]

The Lions retired his number, 85, in his honor, and annually make an award to the most improved player in his name.